Trends in Natural Product Research – PSE Young Scientists’ Meeting Budapest, June 19th-21st, 2019
19
PL-3
doi: 10.14232/tnpr.2019.pl3
Searching for the needle in the haystack – targeted identification of pharmacologically active natural products
Matthias Hamburger
University of Basel, Pharmacenter, Klingelbergstrasse 50, 4056 Basel, Switzerland E-mail: matthias.hamburger@unibas.ch
Natural product-derived or -inspired drug discovery continues to be relevant for the development of innovative medicines. However, screening of extracts and identification of bioactive compounds remain major challenges in natural product- based drug discovery. In recent years a wide range of new technologies and tools have been established in the biosciences and in analytical chemistry that enable new approaches. These new possibilities can be summarized with a few keywords such as:
miniaturization, on-line analysis of complex samples, chemometric data analysis, functional assays, high-content screening, study of molecular modes of action, and systems oriented approaches towards the characterization of drug effects in vitro and in vivo.
Over the past years we explored some of these methodologies in our lab and, as a consequence, established a technology platform for miniaturized natural products- based lead discovery. This platform includes 2D-barcoded liquid extract libraries in 96- well format, HPLC-based micro-fractionation for off-line bioactivity assessment, simultaneous on-line spectroscopy (PDA, HRMS, and MS/MS), and off-line microprobe NMR spectroscopy. The platform is generically applicable with mechanism-based and functional assays in the 96-well MTP format and serves as a core for collaborative projects in various therapeutic areas.
Use of the technology platform will be illustrated with selected examples, including the discovery of new allosteric GABAA receptor modulators and image-based high content screening for compounds targeting key signaling pathways in melanoma. The power of miniaturization will be discussed with the identification of a selectively anti- proliferative cucurbitane derivative from just few mg of a plant extract, and the value of activity profiling data for subsequent structural optimization will be highlighted with the example of the GABAA receptor modulating lead compound SCT-66. We are currently also using our HPLC profiling approach for the assessment of potential cardiac toxicity of herbal drugs. Dehydroevodiamine and hortiamine, two alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, were identified as potent IKr
blockers with proarrhythmic effects in vitro, and in vivo in rodent and dog models.
